Department of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China.
Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P. R. China.
Theranostics. 2022 Jan 1;12(1):59-75. doi: 10.7150/thno.64862. eCollection 2022.
The outcome of sonodynamic immunotherapy is significantly limited by tumor hypoxia. To overcome this obstacle, one common solution is to catalyze the conversion of endogenous HO into O. However, the effectiveness of this strategy is limited by the insufficient concentration of HO in the tumor microenvironment (TME). Herein, we developed a HO economizer for on-demand O supply and sonosensitizer-mediated reactive oxygen species production during ultrasound activation, thereby alleviating hypoxia-associated limitations and augmenting the efficacy of sonodynamic immunotherapy. The HO economizer is constructed by electrostatic adsorption and π-π interactions between the Fe-doped polydiaminopyridine (Fe-PDAP) nanozyme and chlorin e6. By employing a biomimetic engineering strategy with cancer cell membranes, we addressed the premature leakage issue and increased tumor-site accumulation of nanoparticles (membrane-coated Fe-PDAP/Ce6, MFC). The prepared MFC could significantly attenuate the catalytic activity of Fe-PDAP by reducing their contact with HO. Ultrasound irradiation promoted MFC dissociation and the exposure of Fe-PDAP for a more robust O supply. Moreover, the combination of MFC-enhanced sonodynamic therapy with anti-programmed cell death protein-1 antibody (aPD-1) immune checkpoint blockade induced a strong antitumor response against both primary tumors and distant tumors. This as-prepared HO economizer significantly alleviates tumor hypoxia via reducing HO expenditure and that on-demand oxygen-elevated sonodynamic immunotherapy can effectively combat tumors.
声动力学免疫治疗的效果受到肿瘤乏氧的显著限制。为了克服这一障碍，一种常见的解决方案是催化内源性 HO 转化为 O。然而，这种策略的有效性受到肿瘤微环境（TME）中 HO 浓度不足的限制。在此，我们开发了一种 HO 节约器，用于在超声激活时按需供应 O 和声敏剂介导的活性氧的产生，从而缓解与乏氧相关的限制并增强声动力学免疫治疗的效果。HO 节约器是通过 Fe 掺杂的聚二氨基吡啶（Fe-PDAP）纳米酶与叶绿素 e6 之间的静电吸附和π-π相互作用构建的。通过采用具有癌细胞膜的仿生工程策略，我们解决了纳米颗粒（膜包覆的 Fe-PDAP/Ce6，MFC）过早泄漏和肿瘤部位积累不足的问题。所制备的 MFC 可通过减少与 HO 的接触来显著降低 Fe-PDAP 的催化活性。超声辐射促进 MFC 解离并暴露更多的 Fe-PDAP 以提供更强大的 O 供应。此外，MFC 增强的声动力学疗法与抗程序性死亡蛋白-1 抗体（aPD-1）免疫检查点阻断的联合使用，引发了针对原发性肿瘤和远处肿瘤的强烈抗肿瘤反应。这种制备的 HO 节约器通过减少 HO 消耗显著缓解肿瘤乏氧，而按需氧升高的声动力学免疫治疗可以有效地对抗肿瘤。
